Viral vector-mediated reprogramming of the fibroblastic tumor stroma sustains curative melanoma treatment
Sandra S. Ring, Jovana Cupovic, Lucas Onder, Mechthild Lütge, Christian Perez‐Shibayama, Cristina Gil‐Cruz, Elke Scandella, Angelina De Martin, Urs Mörbe, Fabienne Hartmann, Robert Wenger, Matthias Spiegl, Andrej Bešše, Weldy V. Bonilla, Felix Stemeseder, Sarah Schmidt, Klaus K. Orlinger, Philippe Krebs, Burkhard Ludewig, Lukas Flatz
Abstract
The tumor microenvironment (TME) is a complex amalgam of tumor cells, immune cells, endothelial cells and fibroblastic stromal cells (FSC). Cancer-associated fibroblasts are generally seen as tumor-promoting entity. However, it is conceivable that particular FSC populations within the TME contribute to immune-mediated tumor control. Here, we show that intratumoral treatment of mice with a recombinant lymphocytic choriomeningitis virus-based vaccine vector expressing a melanocyte differentiation antigen resulted in T cell-dependent long-term control of melanomas. Using single-cell RNA-seq analysis, we demonstrate that viral vector-mediated transduction reprogrammed and activated a Cxcl13-expressing FSC subset that show a pronounced immunostimulatory signature and increased expression of the inflammatory cytokine IL-33. Ablation of Il33 gene expression in Cxcl13-Cre-positive FSCs reduces the functionality of intratumoral T cells and unleashes tumor growth. Thus, reprogramming of FSCs by a self-antigen-expressing viral vector in the TME is critical for curative melanoma treatment by locally sustaining the activity of tumor-specific T cells.